This invention relates to a process for the preparation of compounds having pharmaceutical activity.
EP-A-0392803 (Beecham Group p.l.c.) discloses certain azabicyclic compounds which enhance acetylcholine function via an action at muscarinic receptors within the central nervous system.
These compounds are therefore of potential use in the treatment and/or prophylaxis of dementia in mammals. Various preparative methods are also disclosed.
We have now developed an improved process for the preparation of one class of the compounds disclosed in EP-A-0392803.
The present invention provides process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
wherein R1 represents 
r represents an integer of 2 to 4, s represents 1 or 2 and t represents 0 or 1;
R2 is a group OR4, where R4 is C1-4 alkyl C2-4 alkenyl or C2-4 alkynyl or a group OCOR5 where R5 is hydrogen or R4; and
R3 is CN;
said process comprising nitrosating a compound of formula (II): 
xe2x80x83wherein R1xe2x80x2 is R1 or a group convertible thereto, and R3xe2x80x2 is an electron withdrawing group, and thereafter converting the resulting xe2x95x90NOH group to xe2x95x90NR2 wherein R2 is as defined in formula (I), converting R1xe2x80x2 and R3xe2x80x2 when other than R1 and R3 to R1 and R3, and thereafter optionally forming a pharmaceutically acceptable salt.
Compounds of formula (I) are capable of existing in a number of stereoisomeric forms including geometric isomers such as syn and anti and, for certain compounds, enantiomers. The different stereoisomeric forms may be separated one from the other by the usual methods.
Compounds of formula (I) having two asymetric centres which have the stereochemical configuration in which the group xe2x80x94C(R3)xe2x95x90NR2 and the (CH2)s bridge are on the same side of the plane of the molecule which contains both bridgehead atoms and the ring carbon atom bonded to the aforesaid group will hereinafter be referred to as having the exo configuration.
If desired, the compounds of formula (I) can be formed into acid addition salts with acids, such as the conventional pharmaceutically acceptable acids, for example hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicylic, citric, lactic, mandelic, tartaric, oxalic and methanesulphonic.
The term pharmaceutically acceptable salt encompasses solvates and hydrates. Thus where compounds of formula (I) or pharmaceutically acceptable salts thereof form solvates or hydrates, these also form an aspect of the invention.
Preferred combinations of (r,s,t) include (2,2,0), (2,1,1), (3,1,1), (2,1,0) and (3,1,0), most preferably (2,2,0).
The groups R4 and R5 in R2 are preferably selected from methyl, ethyl, allyl and propargyl. Suitable values for R2 include methoxy, ethoxy, allyloxy, propargyloxy and acetoxy, preferably methoxy.
Examples of suitable electron withdrawing groups include CN, CO2R and CON(R)2 in which each R is independently H, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl C1-4 alkyl or aryl C1-4 alkyl, wherein aryl groups are selected from optionally substituted phenyl and naphthyl. Suitable examples of substituents on phenyl and naphthyl include one or more, for example 1 to 3, substituents selected from halo, hydroxy, C1-4 alkoxy and C1-4 alkyl. R3xe2x80x2 is preferably CN.
The nitrosation of the compound of formula (II) may be carried out using a nitrosating agent such as an alkylnitrite, preferably a C1-8 alkylnitrite such as t-butyl nitrite or, more preferably, iso-amyl nitrite and a base such as sodium ethoxide or, more preferably, potassium t-butoxide. Dimethylsulphoxide (DMSO) and tetrahydrofuran (THF) are suitable examples of solvents for the nitrosation.
The nitrosation results in a compound of formula (III): 
The xe2x95x90NOH group of the oxime of formula (III) may be converted to xe2x95x90NR2 by conventional routes, for example compounds where R2 is OCOR5 can be made by acylation with an acylating agent such as an acyl halide, for example acetyl chloride. Compounds where R2 is OR4 can be made by alkylation with an alkylating agent such as methyltosylate (methyl p-toluene sulphonate) or an alkyl halide, for example methyl iodide. The alkylation is preferably carried out at a temperature of xe2x88x9220xc2x0 C.-40xc2x0 C., more preferably 0xc2x0 C.-40xc2x0 C., for example 18xc2x0 C.-36xc2x0 C., most preferably below 35xc2x0 C.
R3xe2x80x2 groups other than CN may be converted thereto conventionally, for example conversion, if necessary, to the primary amide followed by dehydration.
Examples of R1xe2x80x2 groups other than R1 include suitable azacyclic precursors which may be cyclised as described in, for example, EP 0392803.
The different steroisomeric forms of compounds of formula (I) may be separated one from the other by the usual methods, for example chromatographic methods. Enantiomers may be separated using chiral resolving agents such as (S)-(+)- and (R)-(xe2x88x92)-1,1xe2x80x2-binaphthyl-2,2xe2x80x2-diyl hydrogen phosphate, or chiral chromatography.
The invention also provides a process for preparing a compound of formula (III) which process comprises nitrosating a compound of formula (II) and thereafter converting R1xe2x80x2 and R3xe2x80x2 when other than R1 and R3 to R1 and R3 and thereafter optionally forming a salt.
Compounds of formula (II) can be prepared from compounds of formula (IV): 
by hydrogenation according to standard procedures.
The reduction of compounds of formula (IV) is preferably carried out by treating a methanolic solution of a compound of formula (IV) with hydrogen under pressure in the presence of Palladium on carbon as a catalyst.
Compounds of formula (IV) may be prepared conventionally, for example as described in EP 0414394, for example by reacting a compound of formula (V). 
with a phosphorus ylide of formula (VI) or (VII): 
in which Ra, Rb and Rc are independently C1-6 alkyl, aryl or aralkyl and R3xe2x80x2 is as defined above, to give a compound of formula (IVa): 
in which R3xe2x80x2 is defined as for formulae (VI) and (VII) and thereafter, where necessary, converting R3xe2x80x2 to CN.
The reaction of a compound of formula (V) with a phosphorus ylide of formula (VI) or (VII) which is equivalent to the conversion of a ketone to an olefin is known as a Wittig Reaction and may be carried out under conditions generally used for such reactions, in particular in the presence of a suitable base such as potassium t-butoxide or, more preferably, potassium hydroxide. Preferably a compound of formula (V) is reacted with a compound of formula (VII) in a Wadsworth Emmonds reaction in which Ra and Rb are each C1-6 alkyl, for example ethyl, and Z is cyano.
Where the R3xe2x80x2 group is a carboxy derivative such as an alkoxycarbonyl group, it may be converted to a cyano group by conventional methods as described above, but preferably before hydrogenation or before nitrosation.
However, as stated above, R3xe2x80x2 is preferably cyano and no conversion is necessary.
Alternatively, compounds of formula (IV) may be prepared by a Knoevenagel condensation (Zh. Obshch. Khim. 1962 32 2935, DE 2323303, CA 1014958 and U.S. Pat. No. 3,857,848).
Intermediates of formula (V) are known compounds (e.g. as described in Thill et al., J. Org. Chem., 1968, 33, 4376) or may be prepared analogously.
Intermediates of formula (VII) are known compounds or may be prepared by the standard Arbuzov reaction (Pure Appl. Chem. 9, 307-335 (1964)) or certain compounds of formula (VII) may be obtained commercially.
Intermediates of formula (VI) are known compounds or may be prepared by analogous methods. Certain compounds of formula (VI) may be obtained commercially.
The compounds of formula (I) are useful in therapy as described in EP-0392803.
The following Examples 1 and 2 illustrates the invention. Reference Examples 1 to 5 illustrate the preparation of intermediates.
To a stirred solution of 3-quinuclidinone (50 g; 0.309 mol) in water (250 ml) was added potassium hydroxide (17.35 g; 0.309 mol). After 15 minutes, diethyl cyanomethyl phosphonate (109.6 g; 0.619 mol) was added with a further 125 ml water. A solution of potassium hydroxide (52.07 g; 0.928 mol) in water (250 ml) was added dropwise over 30 minutes. The reaction was left overnight, saturated with NaCl then extracted into ethyl acetate (6xc3x97200 ml). The organic extracts were combined, dried over anhydrous K2CO3 and concentrated in vacuo to give 3-cyanomethylidene quinuclidine (44 g; 96%, (96% pure-gc)) as a 2:1 mixture of Z:E isomers.
A solution of the product of Reference Example 1 (44.2 g; 0.3 mol) in methanol (625 ml) containing ca 10% Pd/C (4 g) was stirred under hydrogen at 60 psi for 24 hrs. The suspension was filtered through Celite (trade mark), concentrated in vacuo and distilled under reduced pressure to give 3-cyanomethyl quinuclidine (36.2 g; 82%; bpt 118xc2x0 C., 0.3 mmHg).